Exposure of therapeutic and diagnostic medical devices to biological fluids is often accompanied by interfacial adsorption of proteins, cells and microorganisms. Biofouling of surfaces can lead to compromised device performance, increased cost, and in some cases may be life-threatening to the patient. The elimination or minimization of nonspecific biomolecule-material interactions is therefore an integral part of refining the biological performance of current and future biomaterials. Although several antifouling polymer coatings have enjoyed short-term success in preventing protein and cell adsorption on surfaces, none have proven ideal for conferring long-term biofouling resistance. The primary goal of this study is to design and synthesize novel long-lasting antifouling polymers with chemical and structural characteristics optimal for preventing protein fouling at biointerfaces. These polymers consist of two distinct domains coupled together- an anchoring domain inspired by the adhesive proteins secreted by mussels for attachment to marine surfaces, and an antifouling poly(N-substituted glycine) "peptoid" segment designed to resist protein and cellular attachment. Peptidomimetic polymers with a variety of compositions, lengths, and architectures will be synthesized, and high sensitivity protein adsorption experiments will be performed to test the protein resistance of these polymers. The protein adsorption experiments will be both guided by, and confirmed with, theoretical calculations of the systems using a molecular theory that is particularly well-suited to investigating protein interactions with grafted polymers. Such systematic coupled experimental/theoretical investigations are difficult to accomplish with traditional synthetic polymers, but are facilitated in our case by the precise control of peptidomimetic polymer architecture, molecular weight, and composition. Outcomes of this study will include new insights into fundamental properties of antifouling polymers, as well as identification of new biologically inspired polymers capable of limiting protein and cell fouling of therapeutic and diagnostic device surfaces. PUBLIC HEALTH REVELANCE In this study we will combine theoretical and experimental approaches to study the antifouling properties of a new class of biomimetic polymers. When applied to the surface of an object, these polymers are anticipated to enhance the performance of medical devices by providing resistance to fouling by proteins, cells and bacteria.